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Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

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Related in: MedlinePlus

Stimulation trains applied to the pedunculo-pontine tegmentum temporarily abolished alternations of forebrain state.A) Continuous cortical and hippocampal EEG traces and the spectrographic cortical power at 1 Hz demonstrating the effects of stimulation of the pedunculo-pontine tegmental (PPT) region. Subsequent to a series of moderate stimulation trains, which were each effective in promoting an activated forebrain EEG during application, there was a transient suppression of forebrain state alternations. B) Expanded EEG traces from neocortical and hippocampal sites demonstrate that activated patterns were elicited via stimulation and that deactivated patterns follow a stimulation train. C) Scatterplot and linear fit of frequency as a function of the stimulation intensity in the PPT showing a significant (p<0.01) relationship between stimulation intensity and the peak frequency of theta activity recorded in the hippocampus. The frequency was normalized across experiments to the maximal frequency of theta elicited in each. D) Summary of histological findings for the site of stimulation across experiments. Abbreviations: ll: lateral lemniscus, PAG: periaqueductal gray, PPT: pedunculo pontine tegmental nucleus, rs: rubrospinal tract, xscp: decussation of the superior cerebellar peduncle.
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pone-0002004-g011: Stimulation trains applied to the pedunculo-pontine tegmentum temporarily abolished alternations of forebrain state.A) Continuous cortical and hippocampal EEG traces and the spectrographic cortical power at 1 Hz demonstrating the effects of stimulation of the pedunculo-pontine tegmental (PPT) region. Subsequent to a series of moderate stimulation trains, which were each effective in promoting an activated forebrain EEG during application, there was a transient suppression of forebrain state alternations. B) Expanded EEG traces from neocortical and hippocampal sites demonstrate that activated patterns were elicited via stimulation and that deactivated patterns follow a stimulation train. C) Scatterplot and linear fit of frequency as a function of the stimulation intensity in the PPT showing a significant (p<0.01) relationship between stimulation intensity and the peak frequency of theta activity recorded in the hippocampus. The frequency was normalized across experiments to the maximal frequency of theta elicited in each. D) Summary of histological findings for the site of stimulation across experiments. Abbreviations: ll: lateral lemniscus, PAG: periaqueductal gray, PPT: pedunculo pontine tegmental nucleus, rs: rubrospinal tract, xscp: decussation of the superior cerebellar peduncle.

Mentions: As previously reported [36], [37], stimulation trains delivered to sites in or near the PPT resulted in the immediate elicitation of activated patterns in forebrain EEG (Figure 11A, B). As noted by these researchers, an increase in stimulation intensity resulted in a linear increase in the degree of forebrain activation as indexed by the peak frequency of hippocampal theta activity (Figure 11C). More importantly, however, directly following even a short series of stimulation trains, there was a consistent and long-lasting deactivation of forebrain state (33.7±5.0 minutes, n = 4) during which no spontaneous alternations occurred (Figure 11A, D). Thus, stimulation of forebrain-activating brainstem sites implicated in the pacing of cyclical brain state alternations during sleep subsequently disrupts state cycling under urethane anaesthesia. This effect was unlikely to have been mediated by stimulation-induced damage to brain stem sites responsible for forebrain activation since this disruption was only temporary. These effects were also unlikely to have been mediated by prolonged activation of forebrain regions per se since prolonged stimulation of posterior hypothalamic sites, which also potently activated forebrain EEG in a similar way, did not disturb subsequent state alternations (Figure S2).


Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Stimulation trains applied to the pedunculo-pontine tegmentum temporarily abolished alternations of forebrain state.A) Continuous cortical and hippocampal EEG traces and the spectrographic cortical power at 1 Hz demonstrating the effects of stimulation of the pedunculo-pontine tegmental (PPT) region. Subsequent to a series of moderate stimulation trains, which were each effective in promoting an activated forebrain EEG during application, there was a transient suppression of forebrain state alternations. B) Expanded EEG traces from neocortical and hippocampal sites demonstrate that activated patterns were elicited via stimulation and that deactivated patterns follow a stimulation train. C) Scatterplot and linear fit of frequency as a function of the stimulation intensity in the PPT showing a significant (p<0.01) relationship between stimulation intensity and the peak frequency of theta activity recorded in the hippocampus. The frequency was normalized across experiments to the maximal frequency of theta elicited in each. D) Summary of histological findings for the site of stimulation across experiments. Abbreviations: ll: lateral lemniscus, PAG: periaqueductal gray, PPT: pedunculo pontine tegmental nucleus, rs: rubrospinal tract, xscp: decussation of the superior cerebellar peduncle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289875&req=5

pone-0002004-g011: Stimulation trains applied to the pedunculo-pontine tegmentum temporarily abolished alternations of forebrain state.A) Continuous cortical and hippocampal EEG traces and the spectrographic cortical power at 1 Hz demonstrating the effects of stimulation of the pedunculo-pontine tegmental (PPT) region. Subsequent to a series of moderate stimulation trains, which were each effective in promoting an activated forebrain EEG during application, there was a transient suppression of forebrain state alternations. B) Expanded EEG traces from neocortical and hippocampal sites demonstrate that activated patterns were elicited via stimulation and that deactivated patterns follow a stimulation train. C) Scatterplot and linear fit of frequency as a function of the stimulation intensity in the PPT showing a significant (p<0.01) relationship between stimulation intensity and the peak frequency of theta activity recorded in the hippocampus. The frequency was normalized across experiments to the maximal frequency of theta elicited in each. D) Summary of histological findings for the site of stimulation across experiments. Abbreviations: ll: lateral lemniscus, PAG: periaqueductal gray, PPT: pedunculo pontine tegmental nucleus, rs: rubrospinal tract, xscp: decussation of the superior cerebellar peduncle.
Mentions: As previously reported [36], [37], stimulation trains delivered to sites in or near the PPT resulted in the immediate elicitation of activated patterns in forebrain EEG (Figure 11A, B). As noted by these researchers, an increase in stimulation intensity resulted in a linear increase in the degree of forebrain activation as indexed by the peak frequency of hippocampal theta activity (Figure 11C). More importantly, however, directly following even a short series of stimulation trains, there was a consistent and long-lasting deactivation of forebrain state (33.7±5.0 minutes, n = 4) during which no spontaneous alternations occurred (Figure 11A, D). Thus, stimulation of forebrain-activating brainstem sites implicated in the pacing of cyclical brain state alternations during sleep subsequently disrupts state cycling under urethane anaesthesia. This effect was unlikely to have been mediated by stimulation-induced damage to brain stem sites responsible for forebrain activation since this disruption was only temporary. These effects were also unlikely to have been mediated by prolonged activation of forebrain regions per se since prolonged stimulation of posterior hypothalamic sites, which also potently activated forebrain EEG in a similar way, did not disturb subsequent state alternations (Figure S2).

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

Show MeSH
Related in: MedlinePlus